Summary of work: This project aims to understand the molecular mechanisms for the response of the mature and aged neuron to injuries. The unsuccessful response leads to neurodegeneration that is associated with normal aging and various neuropathological disorders. We have found that the cortex responds to loss of subcortical innervation by inducing and secreting amyloid precursor protein (APP), the same protein that has been implicated in the pathology of Alzheimer's disease. The elevated secretion can also be induced by disruption of muscarinic receptor function with the antagonist, scopolamine. In order to understand the normal physiological role of APP, we have characterized its biological properties in cultured PC12 cells. Purified APP acts as a neurotrophic factor whose most dramatic action is to potentiate the neurotrophic activity of NGF. APP stimulates the Insulin signaling pathway, including tyrosine phosphorylation of PI3 kinase and extracellular regulated kinases (ERKs). The presence of APP increases the affinity of PC12 cell membranes for NGF, which suggest that one possible mechanism of APP potentiation is increasing the affinity of its receptors for NGF. These observations suggest that the induction of APP may lead to increased responsiveness of post-synaptic cortical neurons to basal levels of NGF leading to production of new synapses to overcome the lesion effects. Thus, APP may be used in growth factor therapy in conjuction with other agents such as NGF.